Age-related alterations in central cholinergic systems have been linked to impairments in short term memory during normal aging. The elderly are often depressed, and depression has also been demonstrated to produce memory impairment. Thus, the administration of antidepressant compounds which possess anticholinergic properties may further contribute to the observed memory deficits. It would be useful to have an animal model that could test the hypothesis that antidepressants lacking anticholinergic properties are better suited for the elderly who possess or are more susceptible to memory decreasements. This animal model could also be used in subsequent screening of new antidepressants. Rats will be tested using two memory paradigms: a simple one-trial passive avoidance test, and a more complex eight-arm radial maze performance test. Rats of varying ages (young, 2-4 months; middle-aged, 10-13 months; and elderly, 23-26 months) will be used in this study. For memory testing, rats will receive either a vehicle control, scopolamine (a positive anticholinergic control), amitriptyline (an anticholinergic antidepressant), or zimelidine (a new antidepressant lacking anticholinergic effects). It is expected that anticholinergic antidepressants will decrease short-term memory and thus decrease performance in both memory tests. Moreover, aging is expected to further inhibit performance. Since age is known to influence the disposition and resultant pharmacological/toxicological pattern of a number of drugs in humans and animals, this variable must be included in studies designed to examine the effects of drugs often used by the elderly population. Thus, following memory testing, rats will be subjected to a rather complete pharmacokinetic profile following amitriptyline or zimelidine administration. Serum concentration-time data will be obtained in animals of varying ages. In addition, tissue levels of antidepressant drugs and metabolites will be determined. Finally, the hepatic metabolic profile will be assessed using isolated hepatocytes and microsomal preparations. These experiments will enable us to assess the effect of antidepressant drugs on memory and to assess the effect of age on these modifications of short-term memory. Correlations between altered metabolism and distribution of antidepressants in animals of different ages with altered memory responses will be sought.